Compounds of the quindoline family of alkaloids, e.g. quindoline: ##STR1## and cryptolepine: ##STR2## were first synthesized in 1906 (Fichter, F. and Boehringer, R., Chemische Berichte 39, 3932 (1906)).
The natural product cryptolepine was first isolated from the plant Cryptolepis triangularis of the family Periplocaceae in 1929 (Clinquart, E., Bull. Acad. R. Med. Belg. 12, 6237 (1929)). Cryptolepine was reisolated from Cryptolepis sanguinolenta in 1951 (Gellert, E., Raymond-Hamet, Schlittler, E., Helv. Chim. Acta 34, 642 (1951)) and again in 1978 together with quindoline and other uncharacterized alkaloids (Dwuma-Badu, D., Ayim, J. S. K., Fiagbe, N. I. Y., Knapp, J. E., Schiff Jr., P. L., and Slatkin, D. J., J. Pharm. Sci. 67, 433 (1978)). In a study of Sri-Lankan medicinal plants, cryptolepine was identified as the major alkaloid in Sida acuta (Gunatilaka, A. A., Planta Medica 39, 66 (1980)).
Proton and carbon n.m.r. (DMSOd.sub.6) spectra for cryptolepine were assigned by Tackie, A. N., Sharaf, M. H. M., Schiff Jr., P. L., Boye, G. L., Couch, R. C., and Martin, G. E. (J.Heterocycl. Chem. 28, 1429 (1991)); and by Ablordeppy, S. Y; Hufford, C. D.; Borne, R. F., and Dwuma-Badu, D. Planta. Medica. 56, 416 (1990).
A study conducted in 1937 described marked hypothermia in dogs after administration of cryptolepine and noted an antagonistic effect to epinephrine characterized by decreased hypertension and renal vasoconstriction; a lethal dose was determined in guinea pigs after i.p. injection as 120 mg/kg (Raymond-Hamet, C., C. R. Soc. Biol. 126, 768 (1937)). A 1938 study showed a marked and protracted hypotensive response in vasectomized dogs after i.v. administration of cryptolepine (Raymond-Hamet, C., C. R. Acad. Sci., 208, 105 (1938)).
A report claimed that cryptolepine possessed hypotensive and antibacterial properties (Drugs Future, 7(7), 466 (1982). More detailed antimicrobial activities for alcoholic extracts of Cryptolepis sanguinolenta were described (Boakye-Yiadom, K. and Heman-Ackah, S. M., J. Pharm. Sci. 68, 1510 (1979)).
In 1980, a paper described the noradrenoreceptor antagonism of cryptolepine in isolated rat vas deferens (Noamesi, B. K. and Bangbose, S. O. A., Planta Medica 39, 51 (1980)). Cryptolepine's antiinflammatory action was reported in 1981 by the same researchers who identified prostaglandin E2 antagonism as the cause. (Bamgbose, S. O. A. and Noamesi, B. K., Planta Medica, 41, 392 (1981)).
According to the West African Pharmaceutical Federation Cryptolepis sanguinolenta has been widely used in folk medicine for the treatment of malaria, gonorrhoea, and hypertension. The antimalarial activity of Cryptolepis roots is linked to the presence of cryptolepine. As an antiinflammatory agent it is claimed to be as active as piroxicam or indomethacin (IMS Pharmaceutical Marketletter, May 7, 1984, p. 13.)
The effects of cryptolepine alone and in combination with dipyridamole were studied in a mouse model of arterial thrombosis in 1989 (Oyekam, A. O. and Okafor, J. P. O., J. Ethnopharmacology 27, 141 (1989)).
Cryptolepine was found to possess high anti-Candida activity as well as pronounced activity against Gram-positive bacteria. Additionally, weak activity against some Gram-negative bacteria but no antiviral activity was observed (Cimanga, K., Pieters, L., Clayes, M., Vanden Berghe, D., and Vlientick, A. J., Planta Medica 57, Supp. 2, A98, (1991)).
More recently, cryptolepine and related alkaloids were found to possess antimuscarinic activity at the M1, M2, and M3 receptors (Rauwald, H. W., Kober, N. C., Mutschler, E., and Lambrecht, G., Planta Medica, 58, 486 (1992)).
Cryptolepine has been described to have an effect on collagen-induced platelet aggregation and on the mobilization and metabolism of arachidonic acid in a rabbit model (Oyekan, A. O. and Ablordeppey, S. Y., Gen. Pharmacol. 24, 1285 (1993)). Cryptolepine's hypotensive and vasodilator mechanisms of action on perfused rat kidney were further described (Oyekan, A. O., J. Cardiovasc. Pharmacol., 23, 602 (1994)).
Citation or identification of any reference in Section 2 of this application shall not be construed as an admission of prior art to the present invention.
To the knowledge of the inventors, no prior study has described any hypoglycemic activity of extracts of Cryptolepis sp. nor was there any suggestion in the prior art that quindoline alkaloids such as cryptolepine or quindoline would be useful as hypoglycemic agents.